Genetic factors recently have been implicated in rare, familial forms of Parkinson=s disease (PD) and these factors may also function in the more common sporadic form of the disorder. Different genes appear to be involved including alpha-synuclein, parkin, UCH-L1, NR3A2 (NURR1) and DJ-1. Discovery of specific genes involved in the disease is extremely useful in understanding the progression of PD, basic cellular mechanisms, risk factors and provides opportunities to test out new treatment paradigms to halt or delay the progress of the disorder. The general working hypothesis is that mutations in genes involved in PD can be utilized in mouse models to identify early underlying neurotransmission alterations in PD both in the classical nigrostriatal pathway as well as other brain regions critical for the progression of this disorder. The areas studied will be the striatum and the substantia nigra pars compacta [which contains the dopamine (DA) neurons that project to the striatum]. In addition, we hypothesize that areas outside of the striatum and substantia nigra also will display a progression of neuronal dysfunctions that may be linked to PD behaviors. Thus, we also will examine the progression of electrophysiological changes in sensorimotor cortical areas. It is within multiple areas of the brain that physiological changes lead to many of the abnormalities that ultimately cause the symptoms of PD. There are two specific aims: 1) To determine how genetic manipulations known to cause PD in humans when replicated in mice alter the synaptic responses of medium-sized spiny striatal neurons, cortical pyramidal neurons of sensorimotor cortex and their modulation by DA and how the basic electrophysiological properties of these neurons and SN DA neurons are altered; and 2) To determine how knock-out of parkin or over-expressionof alpha-synuclein alters amino acid receptor function and its modulation by activation of DA receptors in medium-sized striatal neurons and cortical pyramidal neurons of sensorimotor cortex. We will examine basic neuronal communication and electrophysiological characteristics and then the changes in the functional properties of glutamate, _- aminobutyric acid (GABA) and DA receptors in the striatum, sensorimotor cortical pyramidal neurons and substantia nigra DA neurons in multiple genetic mouse models. We will use existing mouse models (parkin knock-out and alpha-synuclein over expressing mice) that we have obtained through collaborations as well as the new mouse models generated in the Core and tested in Projects 1 and 2. This project is closely integrated with Project 1 which will examine the progression of behavioral and neuropathological changes in the same mouse models (we will obtain time points for electrophysiological analyses based on data from that project) and Project 2 which will concentrate on the progression of neurochemical changes (we will obtain information on pharmacological approaches from that project). This project also will benefit from information obtained on the association of parkin and alpha-synuclein with components of synaptic vesicles obtained in Project 4. In a similar manner the information we provide will benefit Projects 1, 2, and 4 (by providing specific functional information about synaptic changes) and could provide a bridge for the clinical data obtained in Project 5 by indicating the progression of the types of synaptic changes that occur. Thus, the analyses of these models provides our Center with unique opportunities in a highly interactive, multidisciplinary environment aimed at understanding the progressive mechanisms of cellular dysfunction causing PD. Of primary clinical significance, such analyses can provide novel tools for preclinical testing of neuroprotective strategies.